Process for Enantioselective Synthesis of Single Enantiomers of Modafinil by Asymmetric Oxidation

ABSTRACT

The invention relates to a method for preparing a sulphoxide compound of formula (I) either as a single enantiomer or in an enantiomerically enriched form, comprising the steps of:
         a) contacting a pro-chiral sulphide of formula (II) with a metal chiral complex, a base and an oxidizing agent in an organic solvent; and optionally   b) isolating the obtained sulphoxide of formula (I).       

     
       
         
         
             
             
         
       
         
         
           
             wherein n, Y, R 1 , R 1a , R 2  and R 2a  are as defined in claim  1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/050,666, filed Mar. 18, 2008, which is a continuation of U.S.application Ser. No. 11/082,530, filed Mar. 17, 2005 (U.S. Pat. No.7,368,591, issued May 6, 2008), which is a continuation-in-part of U.S.application Ser. No. 10/943,360, filed Sep. 17, 2004 (U.S. Pat. No.7,317,126, issued Jan. 8, 2008), which in turn claims priority ofEuropean Application No. EP 03292312.0, filed Sep. 19, 2003 and U.S.Provisional Application Ser. No. 60/507,089, filed Oct. 10, 2003. Thedisclosures of these priority applications are incorporated herein byreference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to a process for enantioselectivesynthesis of the single enantiomers or an enantiomerically enriched formof modafinil and other structurally related compounds.

BACKGROUND OF THE INVENTION

Modafinil (C₁₅H₁₅NO₂S) of formula (A), also known as2-(benzhydrylsulphinyl) acetamide or2-[(diphenylmethyl)sulphinyl]acetamide, is a synthetic acetamidederivative with wake promoting activity, the structure and synthesis ofwhich has been described in U.S. Pat. No. 4,177,290.

Modafinil has a stereogenic center at the sulphur atom and thus existsas two optical isomers, i.e. enantiomers.

Modafinil in its racemic form has been approved by the United StatesFood and Drug Administration for use in the treatment of excessivedaytime sleepiness associated with narcolepsy.

U.S. Pat. No. 4,927,855 is related to modafinil enantiomers andparticularly to the levorotary isomer and its use to treat depressionand disorders present in patients suffering from Alzheimer disease.

According to this document, these enantiomers of modafinil are obtainedby a process involving a chiral resolution method, which implies saltformation of the racemate of modafinic acid, also calledbenzhydrylsulphinyl acetic acid, with (−)-α-methylbenzylamine, a chiral,optically pure amine. The diastereoisomers obtained are then separatedand finally one of the separated diastereoisomers is converted into theoptically pure modafinic acid in a hydrolytic, or bond cleavage. Thelevorotary isomer of modafinic acid is thus obtained with very pooryields of about 21% from racemic modafinic acid.

Subsequently, the isolated enantiomer of modafinic acid has to befurther processed by esterification and amidation steps, before thesingle enantiomer of modafinil can be obtained.

Thus, the modafinil enantiomer is obtained with a yield of about 6% fromracemic modafinic acid, calculated on the basis of the yield of eachstep.

Considering alternative ways of obtaining enantiomerically puremodafinil, various metal-catalyzed enantioselective oxidations orstoichiometric transition-metal-promoted asymmetric reactions weredescribed in the literature to prepare chiral sulphoxides by chemicaloxidation of the corresponding sulphides (Kagan H. B. In “CatalyticAsymmetric Synthesis”; Ojima I., Ed. VCH: New York 1993, 203-226;Madesclaire M., Tetrahedron 1986; 42, 5459-5495; Procter D. J., Chem.Soc. PerkinTrans 1999; 835-872; Fernandez I. et al., Chem. Review 2002;A-BC). Metal-catalyzed enantioselective oxidations involve a metalcatalyst complexed with a chiral ligand such as diethyl tartrate,C₂-symmetric diols or C₃-symmetric chiral trialkanolamine titanium(IV)complexes, C₃-symmetric trialkanolamine zirconium(IV) complex, chiral(salen) manganese(III) complex, chiral (salen) vanadium(IV) complex inthe presence of various oxidants such as H₂O₂ tert-butyl hydroperoxide,cumene hydroperoxide. Methods based on chiral oxaziridines have alsobeen used in the chemical oxidation of sulphides.

Some enzymatic methods for the asymmetric synthesis of fine chemicalswere described in Kaber K. in “Biotransformations in Organic Chemistry”,Springer Ed. 3^(rd) ed. 1997 and reviewed by Fernandez I. et al. (Chem.Review 2002, A-BC). As an example, thioethers can be asymmetricallyoxidized both by bacteria [e.g. Corynebacterium equi (Ohta H. et al.Agrig. Biol. Chem. 1985; 49:2229), Rhodococcus equi (Ohta H. et al.Chem. Lett. 1989; 625)] and fungi [Helminthosporium sp., Mortierallaisabeffina sp. (Holland H L. et al. Bioorg. Chem. 1983; 12:1)]. A largevariety of aryl alkyl thioethers were oxidized to yield sulphoxides withgood to excellent optical purity [(Ohta H. et al. Agrig. Biol. Chem.1985; 49:671; Abushanab E. et al., Tetrahedron Lett. 1978; 19:3415;Holland H L. et al. Can. J. Chem. 1985; 63:1118)]. Mono-oxigenases andperoxidases are important class of enzymes able to catalyse theoxidation of a variety of sulphides into sulphoxides (Colonna S. et al.Tetrahedron: Asymmetry 1993; 4:1981). The stereochemical outcome of theenzymatic reactions has been shown to be highly dependant on thesulphide structure.

As an other alternative of the enzymatic approach, optically pure methylarylsulphinylacetates with high enantiomeric excess (>98%) obtained bylipase-catalyzed resolution of the corresponding racemate were alsodescribed (Burgess K. et al. Tetrahedron Letter 1989; 30: 3633).

As an enantioselective oxidation method, an asymmetric sulphideoxidation process has been developed by Kagan and co-workers (Pitchen,P; Deshmukh, M., Dunach, E.; Kagan, H. B.; J. Am. Chem. Soc., 1984; 106,8188-8193). In this process for asymmetric oxidation of sulphides tosulphoxides, the oxidation is performed by using tert-butylhydroperoxide (TBHP) as oxidizing agent in the presence of oneequivalent of a chiral complex obtained from Ti(OiPr)₄/(+) or (−)diethyl tartrate/water in the molar ratio 1:2:1.

The general procedure for sulphide oxidation according to Kagancomprises first preforming the chiral complex at room temperature inmethylene chloride before adding the sulphide. Then, the oxidationreaction is effected at −20° C. in the presence of tert-butylhydroperoxide.

The direct oxidation of a variety of sulphides, notably for arylalkylsulphides into optically active sulphoxides, with an enantiomeric excess(ee), in the range of 80-90%, can be achieved by this method.

More specifically, Kagan and co-workers reported that sulphoxideproducts could be obtained with high enantioselectivity when sulphidesbearing two substituents of very different size were subjected to anasymmetric oxidation. For instance, when aryl methyl sulphides weresubjected to oxidation, it was possible to obtain the aryl methylsulphoxides in an enantiomeric excess (ee) of more than 90%.

Notably, cyclopropylphenyl sulphoxide is formed with 95% ee by thismethod.

However, asymmetric oxidation of functionalized sulphides, notably thosebearing an ester function, was found to proceed with moderateenantioselectivity under these conditions.

Thus, compounds bearing on the stereogenic center, i.e. the sulphuratom, an alkyl moiety with an ester function close to the sulphur atom,such as methylphenylthioacetate, ethylmethylthioacetate andmethylmethylthiopropanoate, are reported with ee of only 63-64% (H. B.Kagan, Phosphorus and Sulphur, 1986; 27, 127-132).

Similarly, oxidation of the aryl methyl sulphides with a methyl esterfunction in the ortho position of the aryl group yields low enantiomericexcess (60%) and yield (50%) as compared to the para substitutedcompound (ee 91%, yield 50%) or to the p-tolyl methyl sulphide (ee 91%,yield 90%) (Pitchen, P et al., J. Am. Chem. Soc., 1984; 106, 8188-8193).

Hence, even when the substituents on the sulphur atom differ in size,the presence of an ester function close to the sulphur atom stronglyaffects the enantioselectivity of the asymmetric oxidation.

These results also show that the enantioselectivity of this processhighly depends on the structure and notably on the functionality of thesubstrate. More specifically, oxidation of sulphides bearing an esterfunction close to the sulphur gives little asymmetric induction.

Similarly, none of the enantioselective reactions so far reported in theliterature deals with substrates bearing an acetamide or acetic acidmoiety directly linked to the sulphur atom.

There have been attempts to improve the enantioselectivity by modifyingsome conditions for asymmetric oxidation of sulphides. For example,Kagan and co-workers (Zhao, S.; Samuel O.; Kagan, H. B., Tetrahedron1987; 43, (21), 5135-5144) found that the enantioselectivity ofoxidation could be enhanced by using cumene hydroperoxide instead oftert-butyl hydroperoxide (ee up to 96%). However, these conditions donot solve the problem of oxidation of sulphides bearing ester, amide orcarboxylic acid functions close to the sulphur atom.

Thus, the applicant obtained crude (−)-modafinil with a typicalenantiomeric excess of at most about 42% with the above method using theconditions described by Kagan H. B. (Organic Syntheses, John Wiley andSons INC. ed. 1993, vol. VIII, 464-467) (refer to Example 17,comparative Example 1 below).

H. Cotton and co-workers (Tetrahedron: Asymmetry 2000; 11, 3819-3825)recently reported a synthesis of the (S)-enantiomer of omeprazole viaasymmetric oxidation of the corresponding prochiral sulphide.Omeprazole, also called5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2pyridinyl)methyl]-sulphinyl]-1H-benzimidazoleis represented by the following formula:

The asymmetric oxidation was achieved by titanium-mediated oxidationwith cumene hydroperoxide (CHP) in the presence of (S,S)-(−) diethyltartrate [(S,S)-(−)-DET]. The titanium complex was prepared in thepresence of the prochiral sulphide and/or during a prolonged time and byperforming the oxidation in the presence of N,N-diisopropylethylamine.An enantioselectivity of >94% was obtained by this method, whereas theKagan's original method gives a modest enantiomeric excess of the crudeproduct (30%).

According to the authors, the improved enantioselectivity of thisprocess applied to omeprazole only is probably linked to the presence ofbenzimidazole or imidazole group adjacent to sulphur, which steers thestereochemistry of formed sulphoxide. The authors also suggested usingthis kind of functionality as directing groups when synthesizing chiralsulphoxides in asymmetric synthesis.

Hence, this publication is essentially focused on omeprazole, apro-chiral sulphide bearing substituents of approximately the same size,and including an imidazole group which is described to play an importantrole in the asymmetric induction.

Therefore, there is a need for an improved enantioselective process forthe manufacture of optically pure modafinil as well as otherstructurally related sulphoxides, notably 2-(benzhydrylsulphinyl)aceticacid and 2-(benzhydrylsulphinyl) alkyl acetate which overcomes thedrawbacks of the prior art and, in particular, allows high yields.

SUMMARY OF THE INVENTION

The present invention provides a novel process for enantioselectivesynthesis of the single enantiomers of modafinil as well as otherstructurally related sulphoxides, in which process a surprisingly highenantioselectivity along with a high yield is obtained.

The novel process is characterized in that a pro-chiral sulphide isoxidized asymmetrically into a single enantiomer or an enantiomericallyenriched form of the corresponding sulphoxide.

The invention also provides a process for preparing a sulphoxide as asingle enantiomer or an enantiomerically enriched form from thecorresponding pro-chiral sulphide with high purity, advantageously witha purity greater than 99.5%-99.8%.

The expression “pro-chiral sulphide(s)”, as used herein, is understoodto designate sulphides which after oxidation present a stereogeniccenter on the sulphur atom. Sulphides having further stereogenic centerselsewhere are thus also herein referred to as “pro-chiral sulphides”.

This novel asymmetric oxidation process allows access to the compoundsof interest with an extremely high enantiomeric excess, even if thecorresponding pro-chiral sulphides are functionalized, i.e. have ester,amide, carboxylic acid or nitrile substituents.

The process is simple with a one step reaction making the processsuitable for large scale production of enantiomeric compounds in a highyield and high enantiomeric excess.

As a further advantage, this process implements low amounts of atitanium compound as a catalyst which is environmentally non-toxic andrelatively low-cost.

Advantageously, modafinil can be obtained as a single enantiomer or inan enantiomerically enriched form, more directly, without having to gothrough a chiral resolution method of modafinic acid.

The invention also provides several processes for preparing modafinil asa single enantiomer or in an enantiomerically enriched form.Advantageously, these processes are limited to three steps or even lesswhen using benzhydrol or benzhydrylthiol as starting material andmodafinil single enantiomer is obtained with high yields.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

It has been found that the asymmetric oxidation of modafinil precursors,in particular diphenylmethylthioacetic acid, the amide and the estersthereof could be achieved with surprisingly high enantioselectivity upto 99.5% by effecting the titanium chiral complex mediated reaction inthe presence of a base.

The invention relates to a method for preparing a sulphoxide compound offormula (I) either as a single enantiomer or in an enantiomericallyenriched form:

wherein:

-   -   Y is —CN, —C(═O)X wherein X is selected from, —NR₃R₄, —OH, —OR₅,        —NHNH₂;    -   R₁, R_(1a), R₂ and R_(2a) are the same or different and are        selected from H, halo, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,        (C₂-C₈)alkynyl, (C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl, —CN, —CF₃,        —NO₂, —OH, (C₁-C₈)alkoxy, —O(CH₂)_(m)NR₆R₇, —OC(═O)R₈,        —OC(═O)NR₆R₇, —C(═O)OR₈, —C(═O)R₈, —O(CH₂)_(m)OR₈,        —(CH₂)_(m)OR₈, —NR₆R₇, —C(═O)NR₆R₇;    -   R₃ and R₄ are the same or different and are each selected from        H, (C₁-C₆) alkyl, hydroxy(C₁-C₈)alkyl, —NHOH or OH, or R₃ and R₄        may also be taken together with the N atom through which R₃ and        R₄ are linked to form a 5 to 7 membered N-heterocyclic group;    -   R₅ represents alkyl, cycloalkyl, aralkyl, alkaryl, or aryl;    -   R₆ and R₇ are the same or different and selected from H,        (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or R₆ and R₇ may also be        taken together with the N atom through which R₆ and R₇ are        linked to form a 5 to 7 membered N-heterocyclic group;    -   R₈ represents H, alkyl, cycloalkyl, aralkyl, alkaryl, or aryl;    -   n is 1, 2 or 3; and    -   m is from 1, 2, 3, or 4;

comprising the steps of:

a) contacting a pro-chiral sulphide of formula (II)

wherein R₁, R₂, R_(1a), R_(2a), Y and n are as defined above,

with a metal chiral ligand complex, a base and an oxidizing agent in anorganic solvent; and optionally

b) isolating the obtained sulphoxide of formula (I).

The method allows to prepare sulphoxides of formula (I) with anenantiomeric excess of generally more than about 80%. Advantageously,preferred enantiomeric excess is of more than 80%, preferably of morethan 90%, more preferably of more than 95%, and most preferably of 99%and more.

The method allows also to prepare sulphoxides of formula (I) with adegree of purity higher than 90%, preferably of more than 98%, morepreferably superior to 99%.

For a pair of enantiomers, enantiomeric excess (ee) of enantiomer E1 inrelation to enantiomer E2 can be calculated using the followingequation:

${\% \mspace{14mu} {enantionmeric}\mspace{14mu} {excess}} = {\frac{\left( {{E\; 1} - {E\; 2}} \right)}{\left( {{E\; 1} + {E\; 2}} \right)} \times 100}$

The relative amount of E1 and E2 can be determined by chiral HPLC (HighPerformance Liquid Chromatography).

The purity refers to the amount of the enantiomers E1 and E2, relativeto the amount of other materials, which may notably, include by-productssuch as sulphone, and the unreacted sulphide. The purity may bedetermined by HPLC as well.

As used herein, the term “about” refers to a range of values ±10% of thespecified value. For example, “about 20” includes ±10% of 20, or from 18to 22.

As used herein, the term “a metal chiral ligand complex” refers to acomplex composed of a metal compound, a chiral ligand and, optionally,water.

The term “chiral ligand” is a group which includes at least one chiralcenter and has an absolute configuration. A chiral ligand has a (+) or(−) rotation of plane polarized light.

In the above definition, “alkyl” means an aliphatic hydrocarbon groupwhich may be straight or branched having 1 to 12 carbon atoms in thechain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain.

“Lower alkyl” means about 1 to about 4 carbon atoms in the chain whichmay be straight or branched. “Branched” means that one or more alkylgroups, such as methyl, ethyl or propyl, are attached to a linear alkylchain. The alkyl may be substituted with one or more “cycloalkyl group”.Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, n-pentyl, cyclopentylmethyl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system of 3to 10 carbon atoms, preferably of about 5 to about 10 carbon atoms.Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl,cycloheptyl and the like.

“Aralkyl” means an aryl-alkyl group wherein the aryl and alkyl are asherein described. Preferred aralkyls contain a lower alkyl moiety.Exemplary aralkyl groups include benzyl, 2-phenethyl andnaphthalenemethyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system of 6 to10 carbon atoms. The aryl is optionally substituted with one or more“ring system substituents” which may be the same or different, and areas defined herein. Exemplary aryl groups include phenyl or naphthyl.

“Alkaryl” means an alkyl-aryl group, wherein the aryl and alkyl are asdefined herein. Exemplary alkaryl groups include tolyl.

“Halo” means an halogen atom and includes fluoro, chloro, bromo, oriodo.

Preferred are fluoro, chloro or bromo, and more preferred are fluoro orchloro.

“Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched having 2to 8 carbon atoms in the chain. Preferred alkenyl groups have 2 to 4carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl are attached to a linear alkenylchain. The alkenyl group may be substituted by one or more halo orcycloalkyl group. Exemplary alkenyl groups include ethenyl, propenyl,n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl,cyclohexyl-butenyl and decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched having 2to 8 carbon atoms in the chain. Preferred alkynyl groups have 2 to 4carbon atoms in the chain. “Branched” means that one or more lower alkylgroups such as methyl, ethyl or propyl are attached to a linear alkynylchain. The alkynyl group may be substituted by one or more halo.Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl,2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.

“Alkoxy” means an alkyl-O— group wherein the alkyl group is as hereindescribed. Preferred alkoxy groups have 1 to 6 carbon atoms in thechain, and more preferably 2 to 4 carbon atoms in the chain. Exemplaryalkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxyand heptoxy.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system of5 to 10 carbon atoms, in which one or more of the carbon atoms in thering system is/are hetero element(s) other than carbon, for examplenitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ringsystem include about 5 to about 6 ring atoms. The “heteroaryl” may alsobe substituted by one or more “ring system substituents” which may bethe same or different, and are as defined herein. A nitrogen atom of anheteroaryl may be a basic nitrogen atom and may also be optionallyoxidized to the corresponding N-oxide. Exemplary heteroaryl andsubstituted heteroaryl groups include pyrazinyl, thienyl, isothiazolyl,oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine,imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl,benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl,imidazopyridyl, benzoazaindole, 1,2,4-triazinyl, benzthiazolyl, furanyl,imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl,isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl,thiazolyl, thienyl and triazolyl. Preferred heteroaryl groups includepyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl and isothiazolyl.

“Hydroxyalkyl” means a HO-alkyl-group wherein alkyl is as hereindefined. Preferred hydroxyalkyls contain lower alkyl. Exemplaryhydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“N-heterocyclic group” means a non-aromatic saturated monocyclic systemof 5 to 7 ring members comprising one nitrogen atom and which cancontain a second heteroelement such as nitrogen, oxygen and sulphur. Theheterocyclyl may be optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. When a second heteroelement selected from a nitrogen or asulphur atom is present, this heteroelement of the N-heterocyclic groupmay also be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Preferred N-heterocyclic group includes piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, and the like. The N-heterocyclicgroup is optionally substituted with one or more “ring systemsubstituent”. Preferred N-heterocyclic group substituents include(C₁-C₄)alkyl, (C₆-C₁₀)aryl, optionally substituted with one or morehalogen atoms, such as the substituent parachlorophenyl.

“Ring system substituents” mean substituents attached to aromatic ornon-aromatic ring systems inclusive of H, halo, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₆-C₁₀)aryl, (C₅-C₁₀)heteroaryl, —CN,—CF₃, —NO₂, —OH, (C₁-C₈)alkoxy, —O(CH₂)_(m)NRR′, —OC(═O)R, —OC(═O)NRR′,—O(CH₂)_(m)OR, —CH₂OR, —NRR′, —C(═O)NRR′, —C(═O)OR and —C(═O)R, whereinR and R′ are H, alkyl, cycloalkyl, aralkyl, alkaryl or aryl or for wherethe substituent is —NRR′, then R and R′ may also be taken together withthe N-atom through which R and R′ are linked to form a 5 to 7 memberedN-heterocyclic group.

In the case of X═OH, the sulphoxide of formula (I) may be obtained as asalt, notably as an alkaline salt, such as a sodium, potassium, lithiumsalt or ammonium salt or pharmaceutically acceptable salts.

“Pharmaceutically acceptable salts” means the relatively non-toxic,inorganic and organic acid addition salts, and base addition salts, ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds. Inparticular, acid addition salts can be prepared by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Exemplary acidaddition salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactiobionate, sulphamates, malonates, salicylates,propionates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methane-sulphonates,ethanesulphonates, benzene-sulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinateslauryl-sulphonate salts, and the like(see, for example, S. M. Berge, et al., <<Pharmaceutical Salts>>, J.Pharm. Sci., 66: p. 1-19 (1977) which is incorporated herein byreference. Base addition salts can also be prepared by separatelyreacting the purified compound in its acid form with a suitable organicor inorganic base and isolating the salt thus formed. Base additionsalts include pharmaceutically acceptable metal and amine salts.Suitable metal salts include the sodium, potassium, calcium, barium,lithium, zinc, magnesium, and aluminum salts. The sodium and potassiumsalts are preferred. Suitable inorganic base addition salts are preparedfrom metal bases which include sodium hydride, sodium hydroxide,potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithiumhydroxide, magnesium hydroxide, zinc hydroxide. Suitable amine baseaddition salts are prepared from amines which have sufficient basicityto form a stable salt, and preferably include those amines which arefrequently used in medicinal chemistry because of their low toxicity andacceptability for medical use. Exemplary base addition salts include theammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzyl-phenethylamine, diethylamine,piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammoniumhydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, e.g., lysine andarginine, and dicyclohexylamine, and the like.

As used herein, “between [ . . . ]-[ . . . ]” refers to an inclusiverange.

According to a preferred aspect, R₁, R₂, R_(1a) and R_(2a) areindependently selected from the group consisting of H and halo, halobeing preferably F.

Preferably, one of R₁, R₂ and/or R_(1a), R_(2a) is H and the other oneis F. The fluorine atom may be located on the ortho, meta, paraposition, the para position being preferred.

Preferably, n is 1.

Most preferably, the sulphoxides prepared by the novel process aresulphoxides of formula (I) in which Y is CN or Y is —C(═O)X.

Preferably, X is —NR₃R₄, —OH, —OR₅, more preferably —NR₃R₄ and mostpreferably —NH₂ or —NHOH.

Preferably, R₅ is alkyl or aralkyl. Preferred R₅ group includes notablymethyl, ethyl, i-propyl, benzyl and tolyl.

Most preferably, the sulphoxide prepared by the novel method ismodafinil, which corresponds to the sulphoxide of formula (I), wherein nis 1, R₁, R₂, R_(1a) and R_(2a) are H and Y is —C(═O)X with X═NH₂.

As used herein, “modafinic acid”, also called“diphenylmethylsulphinylacetic acid”, refers to the compound of formula(I), wherein n is 1, R₁, R₂, R_(1a) and R_(2a) are H and X is OH.

As used herein, an “ester of modafinic acid” refers to a compound offormula (I), wherein n is 1, R₁, R₂, R_(1a) and R_(2a) are H and X is—OR₅.

Step a)

The oxidation reaction is carried out in an organic solvent.Surprisingly, the solvent is not as essential for the enantioselectivityof the oxidation, according to the invention. The solvent may hence bechosen with respect to suitable conditions from an industrial point ofview, as well as environmental aspects. Suitable organic solvents arenotably toluene, ethyl acetate, tetrahydrofuran, acetonitrile, acetoneand methylene chloride and can be readily determined by one skilled inthe art. From an environmental point of view, non-chlorinated solventsare preferred. In this regard, ethyl acetate and toluene areparticularly preferred.

Preparation of the Metal Chiral Ligand Complex

The metal chiral ligand complex is prepared from a chiral ligand and ametal compound.

The metal compound is preferably a titanium, a zirconium, a vanadium ora manganese compound and more preferably a titanium compound.

Thus, preferred metal chiral ligand complexes are notably titanium,zirconium, vanadium or manganese chiral ligand complexes, morepreferably a titanium chiral ligand complex.

The titanium compound is generally a titanium (IV) compound, preferablya titanium (IV) alkoxide, such as, in particular, titanium (IV)isopropoxide or propoxide.

The chiral ligand is a chiral compound capable of reacting with thetitanium compound. Such compounds are preferably chosen from hydroxysubstituted compounds, preferably having more than one hydroxy group.Thus, the chiral ligand is preferably a chiral alcohol, such as aC₂-symmetric chiral diol or a C₃-symmetric chiral triol. The chiralalcohol may be branched or unbranched alkyl alcohol, or an aromaticalcohol.

Preferred chiral ligands are binaphtol, mandelic acid, hydrobenzoin,esters of tartaric acid, such as (+)-dialkyl-L-tartrate or(−)-dialkyl-D-tartrate, preferably (+)-di(C₁-C₄)alkyl-L-tartrate or(−)-di(C₁-C₄)alkyl-D-tartrate, notably (+)-dimethyl-L-tartrate or(−)-dimethyl-D-tartrate, (+)-diethyl-L-tartrate or(−)-diethyl-D-tartrate, (+)-diisopropyl-L-tartrate or(−)-diisopropyl-D-tartrate, (+)-dibutyl-L-tartrate or(−)-dibutyl-D-tartrate and (+)-ditertbutyl-L-tartrate or(−)-ditertbutyl-D-tartrate. Especially preferred are(+)-diethyl-L-tartrate and (−)-diethyl-D-tartrate.

Preferred chiral ligands also include C₃-symmetric trialkanolamines,notably of formula (1):

wherein R is a lower alkyl or aryl, as for example methyl, t-butyl andphenyl. Preferred chiral ligands also include Schiff base of generalformula (2a) or (2b):

wherein R is the same and represents a lower alkyl or aryl, such asmethyl or phenyl, or are attached together to form a cycloalkyl groupsuch as cyclohexyl; R′ is a lower alkyl or alkoxy;

wherein R is a lower alkyl or NO₂;R′ is a lower alkyl or alkoxy.

These Schiff bases may form a chiral ligand complex with the metal,known as chiral (salen)-metal complex.

Preferred examples of metal chiral ligand complexes are C₂-symmetricdiols or C₃-symmetric trialkanolamine titanium (IV) complexes,C₃-symmetric trialkanolamine zirconium (IV) complexes, chiral (salen)manganese (III) complexes, chiral (salen) vanadium (IV) complexes,notably those disclosed in Fernandez et al., American Chemical Society,2002, A-BC.

Especially preferred metal chiral ligand complexes are titanium chiraldiol complexes and most preferably diethyl tartrate titanium (IV)complexes.

The stoichiometry of the metal chiral ligand complex may vary and is notcritical for the invention.

In particular, the ratio of the chiral ligand with respect to the metalcompound may vary from 1 to 4 equivalents and is preferably 2equivalents.

In accordance with a preferred aspect of the invention, the preparationof the metal chiral complex further comprises water. Indeed, it has beenfound that the presence of water in the metal chiral ligand complexfurther improves the enantioselectivity of the reaction.

The amount of water involved in the metal chiral ligand complex may varyfrom 0.1 to 1 equivalent with respect to the titanium compound. In anespecially preferred embodiment, the amount of water ranges from 0.4 to0.8 equivalent with respect to the metal compound.

Thus it is not necessary to pre-dry the reactants. According to anotherparticular embodiment, no water is added, the water present in thereaction mixture being provided only by the residual humidity of thereactants.

The amount of the metal chiral ligand complex used in the process is notcritical. It has however been found advantageous to use less than 0.50equivalent with respect to the pro-chiral sulphide, especially 0.05-0.30equivalent, and most preferably 0.1-0.30 equivalent. Surprisingly, evenvery low amounts of complex, such as for instance 0.05 equivalent may beused in the process according to the invention with excellent results.

The metal chiral ligand complex may be prepared in the presence of thepro-chiral sulphide or before the pro-chiral sulphide is added to thereaction vessel.

According to one preferred embodiment, the preparation of the metalchiral ligand complex is performed in the presence of the pro-chiralsulphide, i.e. the pro-chiral sulphide is loaded into the reactionvessel before the components used for the preparation of the chiralcomplex are introduced.

The reaction time of the metal chiral ligand complex depends on thetemperature.

Indeed, it has been found that the reaction kinetics of the metal chiralligand complex appear to depend on the couple temperature and reactiontime. Thus, the higher the temperature, the lower the reaction time is.Inversely, the lower the temperature, the longer the reaction time is.

As an example, at an elevated temperature, which as used herein means atemperature between 20-70° C., preferably of about 40-60° C., mostpreferably of about 50-55° C., less than two hours are generallysufficient to form the metal chiral ligand complex. As an example, at55° C., the metal chiral ligand complex may be formed in about 50minutes. At a lower temperature, such as at 25° C., the metal chiralligand complex may be formed in about 24 hours.

Introduction of a Base

The asymmetric oxidation according to the invention is carried out inthe presence of a base.

Indeed, the enantioselectivity of the reaction is surprisingly enhancedwhen a base is present during oxidation. Enantioselectivities of morethan 99% may be thus observed. The order of introduction of the base isnot critical, provided that it is added before the oxidizing agent. Thebase may be introduced before or after the pro-chiral sulphide and,preferably after the metal chiral ligand complex is formed.

Preferably, the base is introduced after the metal chiral ligand complexis formed, and after the pro-chiral sulphide is added.

In another preferred embodiment, the base is contacted with the metalchiral ligand complex and the pro-chiral sulphide for few minutes,preferably for at least 3 minutes before adding the oxidant in order toincrease the enantioselectivity.

According to a preferred embodiment of the invention, the base isintroduced at the temperature at which the oxidation reaction is carriedout, hereafter called “oxidation temperature”.

The base should be soluble in the reaction mixture. Preferably, it is anorganic base, such as for instance an amine. Especially suitable basesare amines, preferably tertiary amines, such as triethylamine,N,N-diisopropylethylamine, dimethyl-ethanolamine, triethanolamine and,most preferably, N,N-diisopropyl-ethylamine and triethylamine.

The amount of base added to the reaction mixture should not exceed acertain value, because it may affect the enantioselectivity of thereaction. In particular, an amount of less than 2 equivalents, notablyof 0.5 equivalent with respect to pro-chiral sulphide, especially of0.01 to 2 equivalents, preferably of 0.05 to 0.5 equivalent and mostpreferably of 0.1 to 0.3 equivalent, has proven to be advantageous.

Oxidation

Surprisingly, the process does not require very low temperatures such as−20° C., as described by Kagan and co-workers as essential to obtain agood enantioselectivity. This feature is particularly interesting sincesuch low temperatures result in long reaction times.

The temperature will however be chosen such as to avoid decomposition ofthe reactants and excessive reaction times.

In a preferred embodiment, the oxidizing agent is contacted with thesulphide, the metal chiral ligand complex and the base at a temperaturebetween 0-60° C., preferably 15-40° C. and more preferably at roomtemperature, that is between about 20-25° C.

A suitable oxidizing agent for the asymmetric oxidation may be ahydroperoxide, preferably hydrogene peroxide, tert-butylhydroperoxide orcumene hydroperoxide, and most preferably the latter.

The oxidizing agent is left in contact with the other reactants during asufficient period to achieve satisfactory conversion rate, but not toolong in order not to affect the purity and the enantioselectivity of theproduct obtained.

In a preferred embodiment, the oxidizing agent is left in contact withthe other reactants during about 30 minutes to 3 hours.

The amount of the oxidizing agent is not critical with respect to theenantioselectivity of the reaction. However, an excessive amount ofoxidizing agent may affect the purity of the product obtained byfavouring the formation of sulphone.

An amount of oxidizing agent of less than 2 equivalents relative to theamount of sulphide amide is generally preferred and an especiallypreferred amount is 0.8 to 1.2 equivalents and more preferably 1.0equivalent.

Step b)

The sulphoxide formed during the oxidation reaction may be isolatedaccording to conventional procedures.

Thus, as described in the literature, the reaction mixture may betreated with water or an aqueous sodium hydroxide solution, whichresults in the formation of a gel containing metal salts. This gel maybe filtered off and thoroughly washed with an organic solvent. Thefiltrate may be extracted with an organic solvent. It may also becrystallized in an organic or aqueous solvent to obtain the desiredenantiomer.

According to an advantageous aspect of the invention, the obtainedsulphoxide forms a precipitate that can be directly isolated byfiltration and optionally washed with water or an organic solvent suchas ethyl acetate, toluene, ethanol, methylene chloride. Advantageously,the precipitate is a crystalline and highly pure form. Thus,advantageously, the method avoids cumbersome subsequent treatmentsmentioned above.

Step c)

In accordance with a preferred embodiment, the method further comprisesa step c) of crystallization of the isolated product obtained in stepb).

Such crystallization step may be useful to improve the purity of theisolated product and/or to produce a desired polymorphic form and/or toimprove the enantiomeric excess of the targeted enantiomer and/or toobtain lots with a specific particle size.

In this regard, it can be made reference to WO 2004/060858 in whichpolymorphic forms of modafinil enantiomers were disclosed. As anexample, (−)-modafinil obtained under form II may be converted into formI by a crystallization step c), Forms I and II being as defined in WO2004/060858.

The crystallization may be carried out in organic solvents optionally inadmixture with water. Suitable organic solvent are notably alcohols,ketones, esters, ethers, chlorinated solvents, polar and aproticsolvents and mixtures thereof, or mixture with water.

Examples of alcohols include methanol, ethanol, propanol, isopropylalcohol, tert-butanol, 2 methyl-1-butanol, benzyl alcohol.

Among the chlorinated solvents, dichloromethane may be mentioned.

Among the ketones, acetone, methylethylketone, 2 pentanone,cyclohexanone may be mentioned.

Among the ethers, tetrahydrofuran, dioxane, may be mentioned.

Other suitable solvents can be readily determined by one skilled in theart.

Surprisingly, it has been found that the presence of water in thecrystallization solvent allows to reach an enhanced enantiomeric excessand purity. In addition, a crystallization step using an organicsolvent/water mixture produce a polymorphic form I and advantageouslyallows to reduce the volume of organic solvent utilized in the process.

Thus, preferred crystallization solvents are alcoholic solvents, andmixtures of organic solvents with water, more preferred are mixtures oforganic solvents with water, most preferred are organic solvent mixedwith up to 40% water. Are particularly preferred mixtures of organicsolvents with up to 25% of water.

The product obtained in step b) if needed may also further beenantiomerically enriched. Such methods are known in the art and includenotably preferential crystallization.

Thus in a particular embodiment of the invention, the method furthercomprises a step of preferential crystallization for improving theenantiomeric excess.

Such a method of optical resolution by preferential crystallization of(±) modafinic acid has been disclosed in the French patent applicationWO 2004/060858.

The obtained enantiomer may further be processed to produce lots with aspecific particle size. Conventional methods as milling, sieving,micronization, comminution, separation by weight or by density are knownby those skilled in the art. An appropriate method for the preparationof lots of modafinil having bounded defined particle diameter range isnotably disclosed in WO 2004/006905.

The enantiomers of the sulphoxide compounds of formula (1), wherein Y is—C(═O)X and X is —OH or X is —OR₅, may be converted into theircorresponding amide, that is a sulphoxide compound of formula (I)wherein X=—NH₂.

The enantiomers of modafinic acid or the ester thereof obtained by theabove method may further be converted into the corresponding amide, thatis modafinil enantiomers.

Thus, in accordance with a particular embodiment, esters of modafinicacid enantiomers may be converted into the corresponding modafinilenantiomers by an amidation reaction, notably with ammonia.

Hence, modafinic acid may be converted into modafinil by:

-   -   esterification of the carboxylic acid function by any suitable        method such as, for example, by reaction with a lower alkyl        alcohol, in presence of dimethylsulfate. The obtained        corresponding ester may then be transformed by    -   amidation of the resulting ester by any suitable method, notably        in presence of ammonia.

Such methods have been disclosed notably in U.S. Pat. No. 4,927,855.

In accordance with another particular embodiment, the enantiomers of thesulphoxide compounds of formula (I) wherein Y is CN may be convertedinto their corresponding amide, that is a sulphoxide compound of formula(I) wherein Y is C(═O)X, X being NH₂.

This conversion may be realized by any suitable method known in the art.Examples of such suitable methods are notably oxidation or hydrolysis ofthe nitrile group, for instance, by catalytic phase transfer withperoxides or by basic or acid hydrolysis with an appropriate inorganicbase or acid in mild experimental conditions.

Thus, the desired enantiomer of modafinil may be prepared fromdiphenylmethylsulphinylacetonitrile enantiomers, for example byoxidation with hydrogen peroxide in the presence of tetrabutylammoniumhydrogen sulfate in alkaline conditions or also by direct basic oracidic hydrolysis.

In accordance with another embodiment, the method according to theinvention implements a sulphide of formula (II), wherein Y═C(═O)X, Xbeing NHOH, which may be prepared according to any suitable method knownin the art and notably to the method disclosed in U.S. Pat. No.4,098,824.

In accordance with another embodiment, the method according to theinvention implements a sulphide of formula (IIa) wherein Y is C(═O)X andX is NH₂.

Preparation of Sulphides of Formula (II)

Sulphides of formula (II) may be prepared by any suitable method knownin the art.

By way of example, sulphides of formula (IIa) may be prepared from thecorresponding sulphide of formula (IIb) wherein Y is C(═O)X and X isOR₅.

The sulphide of formula (IIb) may be prepared from an appropriatelysubstituted benzhydrol:

In accordance with a preferred embodiment, the sulphide of formula (IIa)is the sulphide wherein R₁, R_(1a), R₂, R_(2a) are H, n is 1, so calleddiphenylmethylthio-acetamide, which may be prepared from sulphide esterof formula (IIb), in which R₅ is alkyl, preferably (C₁-C₄)alkyl, notablymethyl, so called methyldiphenylmethylthio-acetate (MDMTA).

Such sulphide ester of formula (IIb) and notably MDMTA may be preparedfrom benzhydrol.

In a preferred embodiment, MDMTA is prepared according to the methodcomprising the steps of:

-   -   a1) conversion of benzhydrol into benzhydryl carboxylate,        notably into the benzyhydryl acetate, and    -   b1) conversion of benzhydryl carboxylate, notably the benzhydryl        acetate into MDMTA.

These steps a1) and b1) may be effected by any appropriate method,preferably steps a1) and b1) are performed according to the methoddisclosed in WO 2004/063149.

As an example, modafinil enantiomers may be prepared according to thefollowing reaction steps:

Other routes for preparing diphenylmethylthioacetamide may be used.

By way of example, diphenylmethylthioacetamide, also calledbenzhydryl-thioacetamide, may be prepared from benzhydrol according to aprocess comprising:

-   -   (1) reacting benzhydrol with a suitable acid and thiourea to        form a S-benzhydrylthiouronium salt;    -   (2) reacting the S-benzhydrylthiouronium salt with a suitable        base to form benzhydrylthiol;    -   (3) reacting the benzhydrylthiol with chloroacetamide to form        2-(benzhydrylthio)acetamide.

This process is illustrated by scheme 1.

In the alternative, diphenylmethylthioacetamide may be prepared by theprocess comprising the steps of:

-   -   (1) converting the hydroxyl group of benzhydrol into a leaving        group;    -   (2) converting the obtained product        -   directly into diphenylmethylthioacetamide, or,        -   into alkyl diphenylmethylthioacetate and then into            diphenylmethylthio-acetamide.

This method is illustrated by scheme 2:

Under the terms “leaving group” is understood any group that can beremoved easily by a nucleophilic reactant. Leaving groups may beselected from the group consisting of halogens, such as chloro- andbromo-radicals, or sulphonyl groups, such as methanesulphonyl- orp-toluenesulphonyl-radicals, or acetate radicals.

The first step of this process may be realized by any methods known fromthe person skilled in the art.

As an example, the hydroxyl group of benzhydrol may be converted intochloro- or bromo-radical by reacting benzhydrol with thionyl chloride orthionyl bromide.

As an example, the hydroxyl group of benzhydrol may be converted intomethanesulphonate group or into p-toluenesulphonate group by reactingbenzhydrol respectively with methanesulphonyl chloride orp-toluenesulphonyl chloride.

As an example, the hydroxyl group of benzhydrol may be converted into anacetate radical by reacting benzhydrol with acetyl chloride or aceticanhydride.

As a further alternative, diphenylmethylthioacetamide may be prepared bya process comprising the steps of:

-   -   reacting benzhydrol with alkylthioglycolate in the presence of a        Lewis acid and,    -   reacting the alkyldiphenylmethylthioacetate obtained with        ammonia, as illustrated by scheme 3.

Preferably, the Lewis acid is chosen from ZnCl₂, ZnBr₂, ZnI₂.

Diphenylmethylthioacetamide may also be prepared from benzhydrylthiol.

In that case, diphenylmethylthioacetamide is prepared by a processcomprising the steps of:

(1) reacting benzhydrylthiol with alkylchloroacetate, and,

(2) reacting the obtained alkyldiphenylmethylthioacetate with ammonia.

The process is illustrated by scheme 4:

Another possibility is to prepare diphenylmethylthioacetamide by aprocess comprising the steps of:

-   -   (1) reacting benzhydrylthiol with chloroacetonitrile, and    -   (2) oxidizing or hydrolyzing the obtained        diphenylmethylthioacetonitrile into diphenylmethylthioacetamide.

This process is illustrated by scheme 5.

According to another process, diphenylmethylthioacetamide may beprepared by the process comprising the steps of:

-   -   (1) reacting benzhydrylthiol with a base, such as potassium        hydroxide;    -   (2) reacting the obtained product with a methylene halide;    -   (3) reacting the obtained product with a cyanide salt;    -   (4) oxidizing or hydrolyzing the obtained        diphenylmethylthioacetonitrile into diphenylmethylthioacetamide.

This route is illustrated by scheme 6:

Finally, diphenylmethylthioacetamide may be prepared fromdiphenylmethyl-thioacetic acid by the process comprising:

-   -   (1) reacting diphenylmethylthioacetic acid with an halogenating        agent such as thionyl chloride or a carboxylic acid activating        agent, and    -   (2) reacting the obtained product with NH₃.

This route is illustrated by scheme 7.

Finally, diphenylmethylthioacetic acid may be prepared according to theroute of scheme 1 to 6 notably.

The invention is illustrated more in detail by the following examples.

EXAMPLES Material and Methods Determination of the Enantiomeric Excessin the Examples and Comparative Examples

The enantiomeric excess value in each example given above gives anindication of the relative amounts of each enantiomer obtained. Thevalue is defined as the difference between the relative percentages forthe two enantiomers.

The enantiomeric composition of the obtained sulphoxide has beendetermined by chiral High Performance Liquid Chromatography (HPLC underthe following conditions:

Column: AGP (150×4.0 mm; 5 μm)

Oven temperature: 40° C.

Eluent: sodium acetate+0.5% n-butanol

Flow: 0.9 ml/min

Wavelength: DAD λ=230 nm

As an example:

-   -   Retention time for the        (−)-2-[(diphenyl)methylsulphinyl]acetamide: 6.5 min.    -   Retention time for the        (+)-2-[(diphenyl)methylsulphinyl]acetamide: 8.3 min.        or,

Column: chiralpak AS (250×4.6 mm)

Oven temperature: 40° C.

Eluent: isopropanol/ethanol 85/15

Flow: 0.45 ml/min

Wavelength: 222 nm

As an example:

-   -   Retention time for the        (−)-2-[(diphenyl)methylsulphinyl]acetamide: 27.2 min.    -   Retention time for the        (+)-2-[(diphenyl)methylsulphinyl]acetamide: 14.6 min.        or,

Column: chiralpak AS (250×4.6 mm)

Oven temperature: 30° C.

Eluent: ethanol

Flow: 0.5 ml/min

Wavelength: 220 nm

As an example:

-   -   Retention time for the        methyl(−)-2-[(diphenyl)methylsulphinyl]acetate: 11.4 min.    -   Retention time for the        methyl(+)-2-[(diphenyl)methylsulphinyl]acetate: 10.2 min.

Determination of the Purity in the Examples and Comparative Examples

The purity value in each example is defined as the ratio of the amountof enantiomers obtained after filtration with respect to the totalamount of products present. Studied impurities measured were mainly theunchanged parent compound (pro-chiral sulphide) and the sulphoneresulting from an over oxidation during the process, potentialdegradation products, intermediates of the synthesis of the pro-chiralsulphide.

The purity of the obtained sulphoxide has been determined by HighPerformance Liquid Chromatography (HPLC) under the following conditions:

Column: Zorbax RX C8 (150×4.6 mm; 5 μm) or Zorbax Eclipse XDB C8(150×4.6 mm; 5 μm)

Oven temperature: 25° C.

Eluent:

-   -   A=water+0.1% trifluoroacetic acid    -   B=nitrile acetate+0.1% trifluoroacetic acid with a gradient of        90% A to 100% B in 20 minutes

Flow: 1 ml/min

Wavelength: DAD λ=230 nm (column Zorbax RX C8) 220 nm (column ZorbaxEclipse XDB C8)

As an example (column Zorbax RX C8):

-   -   Retention time for the 2-[(diphenyl)methylsulphinyl]acetamide:        8.8 min.    -   Retention time for the 2-[(diphenyl)methylthio]acetamide: 11.8        min.    -   Retention time for the 2-[(diphenyl)methylsulphonyl]acetamide:        10.5 min.

Examples 1 to 16 Asymmetric synthesis of(−)-2-(diphenylmethyl)sulphinylacetamide General Procedure for Examples1 to 16

Diphenylmethylthioacetamide (7.70 g; 0.03 mol; 1.0 eq) was dissolved inthe solvent (77 mL; 10 vol.). To the solution were added(S,S)-(−)-diethyl-tartrate (1.23 g; 0.006 mol; 0.2 eq) and titanium (IV)tetraisopropoxide (0.85 g; 0.88 mL; 0.003 mol; 0.1 eq) and water (27 μLminus the sum of water present in reactants and solvent alreadyintroduced; 0.0015 mol; 0.05 eq) at 55° C. In these conditions, theresulting chiral titanium complex has the stoichiometry(DET/Ti(OiPr)₄/H₂O: 2/1/0.5) and corresponds to 0.1 eq with respect todiphenylmethylthioacetamide. Stirring was maintained at 55° C. during 50minutes.

After cooling to room temperature (25° C.), were added to the mixturediisopropylethylamine (0.39 g; 0.52 mL; 0.003 mol; 0.1 eq) and cumenehydroperoxide (4.55 g; 5.0 mL; 0.03 mol; 1.0 eq).

After contacting during about an hour, the formed precipitate isisolated by filtration.

All the following experiments were performed in accordance with theconditions of the general procedure, by modifying parameters asindicated in tables 1-17.

Example 1 Influence of the Ratio of the Titanium Chiral Complex withRespect to the Diphenylmethylthioacetamide on the Enantioselectivity andthe Purity of the Asymmetric Oxidation

In this experiment, the ratio of the titanium chiral complex withrespect to the diphenylmethylthioacetamide was varied from 0.05 to 0.3equivalent, the stoichiometry of the chiral titanium complexDET/Ti(O-iPr)₄/water: 2/1/0.4 being maintained constant, all the othersparameters being as defined in the above general procedure. Experimentswere performed in toluene.

TABLE 1 Titanium complex/ Scale E.e. Purity Yield Entry sulphide(equivalent) (mole) (%) (%) (%) 1 0.30/1 0.03 >99.5 >99.5 88.4 2 0.15/10.06 93.6 >99 89.7 3 0.10/1 0.09 93 >99 92 4 0.05/1 0.18 92 95.5 95.4E.e. = enantiomeric excess

In experiments 1 to 4, the enantioselectivity was equal or superior to92%, and increased up to more than 99.5 with the amount of titaniumchiral ligand complex involved in the reaction mixture. The purity wassuperior to 99% except for the lowest ratio titanium chiral ligandcomplex/diphenylmethylthioacetamide. Yields were superior or equal to88.4%.

Example 2 Influence of the Amount of Water on the Enantioselectivity andthe Purity of the Asymmetric Oxidation

In this experiment, the amount of water was varied with respect to thetitanium tetraisopropoxide from 0 to 1 equivalent, all other parametersbeing as defined in the above general procedure. Notably, the ratio ofthe titanium chiral ligand complex was maintained at 0.1 equivalent withrespect to the diphenylmethylthioacetamide. Experiments were performedin toluene.

TABLE 2 Amount of water E.e. Purity Yield Entry (equivalent) (%) (%) (%)1 0 80 — 90.3 2 0.4 93 >99 92 3 0.8 94 >99 88 4 1 91 99.5 90 E.e. =enantiomeric excess; — = Not determined

These results showed that the amount of water had an effect on theenantioselectivity of the reaction. Thus, the best enantioselectivitieswere achieved when an amount of water used comprised between 0.4 and 0.8equivalent. On the opposite, the enantioselectivity drops notably in theabsence of water. A purity superior or equal to 99% and high yields(88%-92%) were obtained.

Example 3 Influence of the Nature of the Solvent on theEnantioselectivity and the Purity of the Asymmetric Oxidation

As reported in table 3, experiments were performed in various solvents,the conditions being the same as in the above general procedure.

TABLE 3 Entry Solvent E.e. (%) Purity (%) Yield (%) 1 Toluene 99.4 99.780 2 Ethyl Acetate 99.5 99.7 73.5 3 Methylene Chloride 98 98.8 61 4Acetonitrile 99.3 98.8 70.2 5 Tetrahydrofuran 99.7 99.6 50.7 6 Acetone99.6 99.2 45.8 E.e. = enantiomeric excess

In all experiments, the sulphoxide amide was obtained with a highenantioselectivity (E.e. equal or superior to 99%) as well as with ahigh purity (purity equal or superior to 98.8%), except when methylenechloride is used as solvent. In this experimental condition theenantioselectivity was slightly lower being, nevertheless, equal to 98%.

Example 4 Influence of the Nature of the Base on the Enantioselectivityand the Purity of the Asymmetric Oxidation

The bases N,N-diisopropylethylamine and triethylamine were compared withregard to the enantioselectivity, the purity and the yield obtainedeither in toluene or in ethyl acetate as solvent. The other parameterswere maintained as defined in the general procedure.

TABLE 4 Purity Yield Entry Base Solvents E.e. (%) (%) (%) 1Diisopropylethylamine toluene 93 >99 92 2 Triethylamine toluene 94 >99.590.3 3 Diisopropylethylamine ethylacetate 99.5 >99.5 73.5 4Triethylamine ethylacetate 99 >99.5 79.2 E.e. = enantiomeric excess

High enantioselectivities and yields were obtained as reported in table4.

In ethylacetate, higher enantioselectivities (>99%) and lower yields(73.5%-79.2%) were obtained with triethylamine anddiisopropylethylamine. On the opposite, in the presence ofdiisopropylethylamine and triethylamine lower enantioselectivities(93-94%) but higher yields (around 90.3%-92%) were observed in toluene.The purity level was similar in both solvents (superior to 99% or 99.5%)when the two bases were added to the reaction medium.

Example 5 Influence of the Amount of Base on the Enantioselectivity andthe Purity of the Asymmetric Oxidation

The ratio of base was varied from 0 to 0.2 equivalent with regard todiphenylmethylthioacetamide.

TABLE 5 Amount of E.e. Purity Yield Entry Base base (eq) Solvents (%)(%) (%) 1 — — toluene 66 >99 86 2 — — ethylacetate 74 >99 70 3Diisopropyl- 0.1 toluene 93 >99 92 ethylamine 4 Triethylamine 0.1ethylacetate 99 >99.5 79.2 5 Triethylamine 0.2 ethylacetate 94.3 >99.878.6 E.e. = enantiomeric excess

In the absence of base, the reaction rate was slow and theenantioselectivity was weak (66%-74% range).

The reaction rate increased with the addition of a base in the reactionmixture. The enantioselectivity was very high when 0.1 equivalent oftriethylamine was added to the reaction mixture and ethylacetate used assolvent. It can be noticed that the enantioselectivity was slightlydecreased when the amount of base used was increased up to 0.2equivalent.

The amount of base has only a little effect on the purity which remainedalways superior to 99%.

In addition, the contact time between the catalyst and the base was afactor increasing the enantioselectivity. A contact time of at least 3minutes between the catalyst and the base increased the enantiomericexcess by about 5%. As an example the enantiomeric excess increased from94.1% (no contact time) to 99.5% (contact time of 3 minutes).

Example 6 Influence of the Temperature of Formation of the TitaniumChiral Ligand Complex on the Enantioselectivity and the Purity of theAsymmetric Oxidation

The titanium chiral ligand complex DET/Ti/H₂O (2/1/0.5) was prepared ata temperature selected in the 25° C. to 70° C. range according to theabove described procedure, the solvent used in the experiments beingethyl acetate. The enantioselectivity and the purity obtained werecompared.

TABLE 6 Temperature Entry (° C.) E.e. (%) Purity (%) Yield (%) 1 2565.6 >99 63.5 2 50 >99.5 99.9 69.6 3 55 99 >99.5 79.2 4 60 >99.5 99.9 735 70 99.7 99.8 62 E.e. = enantiomeric excess

The preparation of the titanium chiral ligand complex at 25° C. during50 minutes results in a lower enantioselectivity. At higher temperature50° C.-70° C., a highly enriched enantiomeric (99%->99.5%) and highlypure (>99.5%-99.9%) form of the sulphoxide is obtained.

Example 7 Influence of the Time of Formation of the Chiral LigandTitanium Complex on the Enantioselectivity and the Purity of theAsymmetric Oxidation

The time of formation of the titanium chiral ligand complex was variedfrom 10 minutes to 50 minutes in ethyl acetate as solvent, the otherparameters being as defined in the above general procedure.

TABLE 7 Entry Time (minutes) E.e. (%) Purity (%) Yield (%) 1 1087.5 >99.5 79.7 2 30 91 99.5 79.2 3 50 99 >99.5 79.2 E.e. = enantiomericexcess

A time of formation of 50 minutes is necessary and sufficient to obtainan enantioselectivity close to superior to 99% as well as a puritysuperior or equal to 99.5%.

As reported in table 8 showing the results of experiments performed at25° C., a prolonged reaction time of at least 24 hours was required toform the titanium chiral ligand complex and to achieve a betterenantioselectivity.

TABLE 8 Entry Temperature (° C.) Time E.e. (%) Purity (%) Yield (%) 1 2550 min 65.6 >99 63.5 2 25  1 hr 78.4 99.1 72.0 3 25  3 hrs 86.4 99.474.6 4 25  8 hrs 89.6 99.0 75.8 5 25 14 hrs 92.2 99.5 74.6 6 25 24 hrs94.2 97.0 85.5 E.e. = enantiomeric excess

Example 8 Influence of the Temperature of the Oxidation Reaction on theEnantioselectivity and the Purity of the Asymmetric Oxidation

The oxidation step, corresponding to the introduction of the oxidizingagent, was carried out at a temperature selected from 0° C. to 55° C. inethyl acetate as solvent, the other parameters being as defined in theabove general procedure.

TABLE 9 Entry Temperature E.e. % Purity % Yield (%) 1  0° C. 99.7 99.752.6 2 10° C. 99.5 99.7 65.0 3 20° C. 99.5 99.8 73.9 4 25° C. 99 >99.579.2 5 55° C. 94.3 97.8 81.8 E.e. = enantiomeric excess

All experimental conditions lead to high enantiomeric excesses and highpurities, in the 94.3%-99.7% range and in the 97.8%-99.7% range,respectively.

At a temperature of 55° C., the enantiomeric excess was decreasedslightly by about 5% from 99.5% to 94.3%. The sulphoxide was producedwith a higher yield (81.8%) but with a slightly lower purity (97.8%).

Example 9 Influence of the Addition Time of the Oxidizing Agent on theEnantioselectivity and the Purity of the Asymmetric Oxidation

The impact of addition time of the oxidizing agent on theenantioselectivity of the reaction was tested. Thus, cumenehydroperoxide (CuOOH) was added upon either 5 or 40 minutes (in thisassay, the oxidant was diluted in ethylacetate), the other parametersbeing as defined in the above general procedure and the reactionperformed in ethyl acetate.

TABLE 10 Entry Time (minutes) E.e. (%) Purity (%) Yield (%) 1 5 99 >99.579.2 2 40* >99.8 99.5 64.7 E.e. = enantiomeric excess; *CuOOH wasdiluted in ethyl acetate.

The addition time of the oxidizing agent did not have a significantinfluence on the enantioselectivity or the purity.

Example 10 Influence of the Nature of the Chiral Ligand on theEnantioselectivity and the Purity of the Asymmetric Oxidation

Table 11 reports chiral ligands and the solvents assayed, the otherparameters being as defined in the above general procedure.

TABLE 11 Entry Chiral ligand Solvent E.e. (%) Purity (%) Yield (%) 1(S,S)-(−)-DET ethyl acetate 99 >99.5 79.2 2 (S,S)-(−)-DETtoluene >99.5 >99.5 88.4 3 (R,R)-(+)-DET toluene 98.6 >99.5 98.5 4(S,S)-(−)-DIT ethyl acetate 92.5 99.2 73.9 E.e. = enantiomeric excess;DET = diethyl tartrate; DIT = Diisopropyl tartrate

In the experimental conditions selected, an enantioselectivity equal to92.5% or in the 98->99.5% range and a purity in the 99.2->99.5% rangewere obtained when using diethyltartrate or diisopropyl tartrate aschiral ligands.

Example 11 Influence of the Order and of the Temperature of Introductionof Reagents on the Enantioselectivity and the Purity of the AsymmetricOxidation

The following experiments were performed in ethyl acetate. Quantitiesused were as defined in the general protocol above.

TABLE 12 Reagents introduction: order and temperature E.e. Purity YieldEntry 1/T 2/T 3/T 4/T 5/T 6/T % % % 1 DET/ SA/ Ti(OiPr)₄/ H₂O/ Et₃N/CHP/ 99.4 99.7 67.2 20° C. 20° C. 50° C. 50° C. 20° C. 20° C. 2 DET/ SA/Et₃N/ Ti(OiPr)₄/ H₂O/ CHP/ 99.6 99.8 78.9 20° C. 20° C. 50° C. 50° C.50° C. 20° C. 3 DET/ SA/ Ti(OiPr)₄/ Et₃N/ H₂O/ CHP/ 99.6 99.7 77.6 20°C. 20° C. 50° C. 50° C. 50° C. 20° C. 4 DET/ Ti(OiPr)₄/ H₂O/ SA/ Et₃N/CHP/ 98.8 99.6 64.2 20° C. 50° C. 50° C. 50° C. 20° C. 20° C. 5 DET/Ti(OiPr)₄/ H₂O/ SA/ Et₃N/ CHP/ 99.0 99.6 69.0 20° C. 50° C. 50° C. 20°C. 20° C. 20° C. 6 DET/ Ti(OiPr)₄/ H₂O/ Et₃N/ SA/ CHP/ 98.6 99.4 68.420° C. 50° C. 50° C. 20° C. 20° C. 20° C. 7 DET/ Ti(OiPr)₄/ H₂O/ Et₃N/SA/ CHP/ 98.8 99.7 77.5 20° C. 50° C. 50° C. 50° C. 50° C. 20° C. 8 DET/SA/ Ti(OiPr)₄/ H₂O/ Et₃N/ CHP/ 99.0 99.7 78.1 20° C. 20° C. 50° C. 50°C. 50° C. 20° C. E.e. = enantiomeric excess; DET = (S,S)-(−)diethyltartrate; Ti(OiPr)₄ = titaniumtetraisopropoxide; SA = sulphide amide;Et₃N = triethylamine; CHP = cumene hydroperoxide.

The reagents introduction order and temperature influenced only slightlythe enantioselectivity (98.6-99.6% range) and the purity (99.4-99.8%range) of the asymmetric oxidation of the sulphide amide studied,provided that the triethylamine was added before the oxidant.

Example 12 Influence of the Contact Time of the Oxidant in the ReactionMixture on the Enantioselectivity and the Purity of the AsymmetricOxidation

The experiment was performed according to the general procedure in ethylacetate as solvent. The contact time between the oxidant and thereaction mixture was studied at room temperature.

TABLE 13 Sulphone Sulphide Entry Contact time E.e. (%) Purity (%) amide(%) amide (%) 1 30 min 99.6 99.66 0.04 0.28 2 1 hr 99.6 99.77 0.05 0.173 2 hrs 99.6 99.75 0.06 0.17 4 3 hrs 98.8 99.78 0.06 0.15 5 4 hrs 97.099.73 0.07 0.16 6 5 hrs 96.4 99.83 0.07 0.09 7 6 hrs 96.8 99.82 0.070.09 8 20.5 hrs 95.5 99.77 0.10 0.12 9 24 hrs 94.6 99.85 0.08 0.07 10 48hrs 94.2 99.85 0.09 0.06 E.e. = enantiomeric excess

The global yield of the reaction was 76.8%. The contact time between theoxidant and other reagents weakly influence the enantioselectivity ofthe reaction which is slightly decreased with time although remainingacceptable (> to 94%).

The purity remains high (increasing from 99.66% to 99.85%) with time.The levels of sulphone amide increased slightly from 0.04% to 0.1% overa 48 hour period while the sulphide amide decreased from 0.28% to 0.1%with time. The best ratios of enantioselectivity over purity wereobtained within 3 hours post the oxidant introduction in the reactionmixture.

Example 13 Influence of the Quantity of Oxidant on theEnantioselectivity and the Purity of the Asymmetric Oxidation

In the general experimental procedure defined above, the quantity ofoxidant was varied between 0.9 and 2 equivalents with respect to thequantity of sulphide amide taken as 1 equivalent. The solvent used wasethyl acetate.

TABLE 14 CuOOH/ Ee Purity Sulphone Sulphide Yield Entry sulphide amide %% amide % amide % % 1 0.9/1 99.2 98.88 0.08 0.91 72.8 2  1/1 99.6 99.880.02 0.10 72 3 1.1/1 99.6 99.87 0.13 <DL 77.5 4  2/1 99.5 99.29 0.70 <DL67.8 E.e. = enantiomeric excess; CuOOH = cumene hydroperoxide; DL =detection limit

Results reported in table 14 showed that the enantioselectivity of thereaction was high, being equal or superior to 99.2%. The purity was highas well, being, in particular, equal to 99.87% when 1 and 1.1 equivalentof oxidant with respect to the sulphide amide (1 equivalent) were addedin the reaction mixture. For 1 equivalent of oxidant, the percentage ofsulphone detected was as low as 0.02%. The amount of sulphide was belowthe detection limit for 1.1 to 2 equivalents of oxidant.

Example 14 Influence of the Quantity of Chiral Ligand on theEnantioselectivity and the Purity of the Asymmetric Oxidation

In the general experimental protocol defined above, the quantity ofchiral ligand [(S,S)-(−)diethyl tartrate] was varied between 1 and 2equivalents with respect to the quantity of titanium isopropoxide takenas 1 equivalent in the chiral ligand titanium complex. The solvent usedwas ethyl acetate.

TABLE 15 Entry DET/Ti/H₂O E.e. (%) Purity (%) Yield (%) 1 2/1/0.5 99.499.7 71.4 2 1.5/1/0.5 94.8 99.7 76.9 3 1/1/0.5 69.4 — — E.e. =enantiomeric excess; DET = [(S,S)-(−)diethyl tartrate; Ti =titaniumisopropoxide; — = not determined

An enantioselectivity close to 95% or higher than 99% and a puritysuperior to 99% were obtained for a chiral ligand titanium complexstoichiometry in the 1.5/1/0.5-2/1/0.5 range.

Example 15 Reproducibility of the Asymmetric Oxidation Reaction

The reproducibility of the asymmetric oxidation reaction of thediphenylmethyl-thioacetamide as defined in the general protocol abovewas assessed repeatedly in four separate experiments in ethyl acetateused as solvent.

TABLE 16 Sulphide Sulphone Entry E.e. (%) Purity (%) amide (%) amide (%)Yield (%) 1 99.6 99.84 0.10 0.05 73.3 2 99.6 99.86 0.05 0.09 74 3 99.699.79 0.13 0.05 73.9 4 99.6 99.88 0.10 0.02 72 E.e. = enantiomericexcess

As shown in table 16, the reproducibility of the results is high. Theenantioselectivity was repeatedly found superior or equal to 99.6% andthe purity superior or equal to 99.8%. The levels of impurities werevery low with only measurable levels of the sulphone amide in the0.02-0.09% range and of the remaining parent compound sulphide amide inthe 0.05-0.13% range. Search for other impurities as for example thecorresponding sulphide acid or ester or their sulphone derivatives wasunsuccessful.

Example 16 Influence of the Structure of Pro-Chiral Sulphide Derivativeson the Enantioselectivity and the Purity of the Asymmetric Oxidation

The following pro-chiral sulphide derivatives were assayed in theexperimental conditions as defined in the general procedure above andethyl acetate as solvent.

TABLE 17 Con- Pro-chiral sulphide derivatives E.e. version Entry R1a R1R2a R2 n Y % rate (%) 1 H H H H 1 CONH₂ 99.6 ~100 2 4-F 4′-F H H 1 CONH₂92.5 99 3 H H H H 1 CONHCH₃ 96.4 ~97 4 H H H H 1 CONHCH₂Ph ~93 ~97 5 H HH H 1 CN ~92 ~94

Results indicated that the protocol may be applied to the compounds,giving a good enantioselectivity as high as 92%-99.6% in most cases anda good conversion rate in the 94%-100% range. In addition acrystallization step may be applied to the isolated end product of thereaction in order to increase the enantiomeric conversion and/or thepurity of the desired enantiomer.

Example 17

Example 17 corresponds to the comparative Examples 1 to 3. The generalprocedure used to prepare sulphoxides was as described above:

General Procedure

Oxidation of sulphide in accordance with the method described by Kaganet al. Organic Syntheses, John Wiley and Sons INC. ed., 1993; vol. VIII,464-467.

Water (0.27 mL, 0.015 mol, 1.0 eq) was added dropwise at roomtemperature (20° C.) to a solution of diethyltartrate (DET) (6.19 g,0.03 mol, 2.0 eq) and titanium (IV) isopropoxide (4.26 g, 4.43 mL, 0.015mol, 1.0 eq) in 125 mL of anhydrous methylene chloride, under nitrogen.Stirring was maintained until the yellow solution became homogeneous (30min) and the sulphide (0.03 mol, 2.0 eq) was added. The solution wascooled to −30° C. and left in contact for 50 minutes at −30° C. Then,cumene hydroperoxide (4.57 g, 5.0 mL, 0.03 mol, 2.0 eq) was added andthe mixture was kept at −25° C. for 15 hours. After this time, 5 mL ofwater were added, and the solution was stirred during 1 h 30. The mediumwas filtered on clarcel and the filtrate worked up depending on thesulphoxide obtained. As an example, when the sulphoxide ofdiphenylmethylthioacetic acid was generated, the compound was extractedwith 3×100 mL of an aqueous solution of K₂CO₃ (0.6 M). The aqueousphases were collected, filtered on clarcel, acidified by addition of 150mL of an aqueous solution of chlorhydric acid 4N (pH≈1). The precipitateformed is filtered on a fritted glass, rinsed with water and then driedin vacuo at 35° C.

Comparative Example 1 Enantioselectivity of Asymmetric Oxidation ofSulphides of Formula (II) with n=1 According to X=—NH₂—OCH₃, —OH

The above general procedure for comparative examples was applied todiphenylmethylthioacetamide, methyldiphenylmethylthioacetate ordiphenylmethyl-thioacetic acid as sulphide, and by using either(R,R)-DET or (S,S)-DET.

TABLE 18 Conversion Precursor DET Ee % rate (%)Diphenylmethylthioacetamide (R,R)-(+)-DET 42 90Methyldiphenylmethylthioacetate (R,R)-(+)-DET 10 40Diphenylmethylthioacetic acid (R,R)-(+)-DET 50 70Diphenylmethylthioacetic acid (S,S)-(−)-DET 50 83

Comparative Example 2 Influence of the Amount of Oxidizing Agent on theEnantioselectivity of Oxidation of Diphenylmethylthioacetic Acid

The above general procedure for comparative examples was applied todiphenylmethylthioacetic acid by varying the amount of cumenehydroperoxide from 1 to 4 equivalents.

TABLE 19 Cumene Conversion rate Hydroperoxide (eq) Ee (%) (%) 1 50 83 250 92 4 50 97

The increase of the amount of the oxidizing agent allows to enhance theconversion rate of sulphide into sulphoxide but does not improve theenantioselectivity of the reaction, according to the Kagan's procedure.

Comparative Example 3

Influence of the Stoichiometry of the Titanium Chiral Complex on theEnantioselectivity of Oxidation of Diphenylmethylthioacetic Acid

The above general procedure for comparative examples was applied todiphenylmethylthioacetic acid by varying the stoichiometry of the chiraltitanium complex (S,S)-(−)-DET/Ti/H₂O.

TABLE 20 (S,S)-(−)-DET/Ti/ Conversion rate H₂O Ee (%) (%) 2/1/1 50 922/1/0 0 97 4/1/0 0 97

The water is necessary to obtain an enantioselectivity, according to theKagan's procedure.

Examples 18 to 24

Examples 18 to 23 correspond to examples of optional re-worked processesthat may be applied to the crystallized end product resulting from theasymmetric oxidation and isolated by filtration in order either toobtain:

-   -   an enantiomerically enriched form of the targeted enantiomer,    -   a specific polymorphic form of the enantiomer,        and/or

to achieve a higher degree of purity by removing impurities as, asexample, the initial pro-chiral sulphide and/or the suphone.

As used hereafter, the forms I, II and IV refer to the polymorphic formsof (−)-modafinil disclosed in WO 2004/060858.

Example 18

A suspension of (−)-modafinil enantiomerically enriched (5 g; 0.018mole) and ethanol 95% (20 to 25 mL; 4 to 5 volumes) was reflux understirring for 5 minutes. The solution obtained was cooled first to roomtemperature (25° C.) and then kept at 4° C. for 1 or 2 hours. Thecrystallized sulphoxide was filtered under vacuum, washed with coldethanol (95%) and dried under vacuum in an oven at 40° C. Results arereported in table 21.

TABLE 21 Initial Final E.e. Purity Polymorphic E.e. Purity PolymorphicEntry (%) (%) Form (%) (%) Form 1 93.0 — — 98.6 — — 2 91.6 — — 99.1 — —3 94.0 — — 98.4 99.5 I 4 98.8 99.4 II 99.0 99.6 I 5 95.4 99.9 — 97.299.8 I 6 96.8 99.5 I 98.0 99.7 I E.e. = enantiomeric excess; —: notdetermined

As shown in table 21, the enantiomeric excess was increased bycrystallization in an ethanol/H₂O (95/5) mixture. Such treatments leadto (−)-modafinil polymorphic form I.

Example 19

Crystallization of (−)-modafinil enantiomerically enriched was performedin Tetrahydrofuran/H₂O (95/5) and acetone/H₂O (95/5) mixtures accordingto the experimental conditions described in Example 18.

TABLE 22 Initial Final Sul- Sul- Sul- Sul- phide phone phide phone E.e.amide amide E.e. amide amide Entry Solvent (%) (%) (%) (%) (%) (%) 1THF/H₂O 94.2 1.10 1.90 99.8 ND 0.40 (95/5) 2 THF/H₂O 94.8 0.12 0.11 99.4ND 0.10 (95/5) 3 Acetone/ 94.8 0.06 0.24 98.2 ND 0.30 H₂O (95/5) E.e. =enantiomeric excess; ND: not detectable

Results reported in table 22 show an increase of the enantiomeric excessas well as a decrease of the pro-chiral sulphide amide below thedetection limit. The quantity of sulphone amide was decreased as well.

Example 20

A suspension of (−)-modafinil enantiomerically enriched (12.15 g; 0.044moles) and THF (122 mL) was slowly heated under stirring untildissolution is complete and then refluxed. The solution was cooled at acontrolled rate of −0.5° C./min to 0° C. and kept at this temperaturefor 45 minutes. The crystallized sulphoxide was filtered and dried at40° C. under vacuum. Results are reported in table 23.

Yield: 77.1%

TABLE 23 Initial Final E.e. Purity Sulphone Sulphide E.e. PuritySulphone Sulphide (%) (%) amide (%) amide (%) (%) (%) amide (%) amide(%) 99.2 98.50 0.25 0.28 100 99.71 0.05 0.01 E.e. = enantiomeric excess

In the above described experimental conditions, the addedcrystallization step increased the enantiomeric excess and the globalpercent of purity, while decreasing the levels of sulphone formed aswell as the remaining untreated pro-chiral sulphide amide levels.

Example 21

To a 250 mL flask containing 180 mL of dichloromethane, (−)-modafinilenantiomerically enriched (10 g; 0.036 mole) form II was added. Themixture was heated to reflux and stirred until a solution was obtained.125 mL of solvent were condensed in a dean-stark extension. Theremaining suspension was cooled to room temperature and then placed inan ice-water bath for 1 hour. The crystallized sulphoxide was filteredoff and dried at 40° C. under vacuum.

Yield: 84.6%.

TABLE 24 Initial Final E.e. Purity Sulphone Sulphide E.e. PuritySulphone Sulphide (%) (%) amide (%) amide (%) (%) (%) amide (%) amide(%) 99.2 98.50 0.25 0.28 100 99.71 0.03 0.02 E.e. = enantiomeric excess

In the above described experimental conditions, the crystallization stepincreased the purity level. The sulphone amide and the pro-chiralsulphide amide levels were decreased after this additional treatment.The final sulphoxide was crystallized as the polymorphic form IV.

Example 22

A suspension of (−)-modafinil enantiomerically enriched (10 g; 0.036mole) in acetonitrile (100 mL) was heated up to reflux under stirring(350 rpm) until complete dissolution. Then, the solution was cooled to0° C. at a rate of −0.5° C./min and stirred (350 rpm) for about 1 hour.The crystallized sulphoxide was filtered off and dried at 40° C. undervacuum.

Yield: 69.3%.

TABLE 25 Initial Final E.e. Purity Sulphone Sulphide E.e. PuritySulphone Sulphide (%) (%) amide (%) amide (%) (%) (%) amide (%) amide(%) 99.2 98.50 0.25 0.28 100 99.90 0.02 0.03 E.e. = enantiomeric excess

The (−)-diphenymethylsulphinylacetamide was obtained with a 100%enantiomeric excess and the sulphone amide and the pro-chiral sulphideamide levels were decreased after the additional crystallizationtreatment.

Example 23

A suspension of (−)-modafinil enantiomerically enriched (10 g; 0.036mole) in ethyl acetate (150 mL) was heated to reflux under stirring (350rpm). Then methanol (25 mL) was added to achieve complete dissolution.Then, the solution was cooled to 0° C. at a rate of −0.5° C./min andstirred (350 rpm) for 45 minutes. The crystallized sulphoxide wasfiltered off and dried at 40° C. under vacuum.

Yield: 38%.

TABLE 26 Initial Final E.e. Purity Sulphone Sulphide E.e. PuritySulphone Sulphide (%) (%) amide (%) amide (%) (%) (%) amide (%) amide(%) 99.2 98.50 0.25 0.28 99.8 99.54 0.04 0.03 E.e. = enantiomeric excess

As reported in table 26, the crystallization step in ethyl acetate andmethanol mixture decreased the sulphone amide and the pro-chiralsulphide amide levels by 84 and 89%, respectively.

Example 24 Synthesis of the Diphenylmethylthioacetamide

A reactor equipped with an impeller stirrer and a gas introduction tubewas charged with methyldiphenylmethylthioacetate (100 g; 1 equivalent)and methanol (300 mL; 3 volumes) at room temperature. The mixture washeated to 35° C. Ammonia (7 equivalents) was introduced within 3 hours,and the mixture contacted at 35° C. for 16 hours before adding 3equivalents of ammonia. When the reaction was completed, the mixture wascooled to 25° C. and water (90 ml; 0.9 volume) added. The mixture wasfiltered and dried under vacuum.

Yield: 83%

¹H-NMR (CDCl₃, 400 MHz): δ H 7.41 (d, 4H, H arom), 7.32 (t, 4H, H arom),7.25 (t, 2H, H arom), 6.53 (s, 1H, NH₂), 6.22 (s, 1H, NH₂), 5.18 (s, 1H,CH), 3.07 (s, 2H, CH₂).

Example 25 Asymmetric Synthesis ofmethyl(−)-2-[(diphenyl)methylsulfiny]acetate

General Procedure

In a 100 mL vessel (AutoMATE-HEL), methyldiphenylmethylthioacetate (5 g;18.4 mmol; 1.0 eq) was dissolved in toluene (20 mL; 4 vol.). To thesolution were added (R,R)-(+)-diethyl-tartrate (1.9 mL; 11.0 mmol; 0.6eq) and titanium (IV) tetraisopropoxide (1.7 mL; 5.5 mmol; 0.3 eq) at54° C. In these conditions, the resulting chiral titanium complex hadthe stoichiometry: DET/Ti(OiPr)₄:2/1 and corresponded to 0.3 eq withrespect to methyldiphenylmethylthioacetate under stirring. Stirring wasmaintained at 54° C. during at least 60 minutes.

After cooling to room temperature (30° C.), triethylamine (1.6 mL; 11.0mmol; 0.6 eq) was added to the mixture and contacted for 20 minutes.Then, cumene hydroperoxide (3.4 mL; 18.4 mmol; 1.0 eq) was slowly addedwithin 6 to 11 minutes. The formation of the reaction end productmethyl(−)-2-(diphenyl-methylsulfinyl)acetate was assessed over a 24hours period. The enantiomeric excess was measured repeatedly by HPLC(refer to material and method section).

All the following experiments were performed in accordance with theconditions of the general procedure, by modifying parameters asindicated in table 27.

TABLE 27 E.e. Conversion rate Entry General Protocol modifications (%)(%) 1 — 83.5 87.9 2 Triethylamine (2.6 mL; 1 eq) 83.2 83.2 3Triethylamine (3.9 mL; 1.5 eq) 84.1 71.4 4 Cumene hydroperoxide (4 mL;1.2 eq) 81.3 87.5 5 Oxidation reaction temperature: 35° C. 73.8 77.3

As shown in table 27, the methyl(−)-2-(diphenylmethylsulfinyl)acetatewas formed with a high enantioselectivity, superior to 81%, and a highconversion rate in the above conditions.

1. A three-step method for preparing (R)-modafinil having anenantiomeric excess of at least about 99.0%, wherein the steps comprise:a. dissolving (R)-modafinil having an enantiomeric excess of about 91.6%to about 98.8% in a solvent to form a solution; b. crystallizing(R)-modafinil from the solution; and c. isolating the crystallized(R)-modafinil, wherein the isolated (R)-modafinil has an enantiomericexcess of at least about 99.0%.
 2. The method of claim 1, wherein thesolvent comprises ethanol, tetrahydrofuran, acetone, dichloromethane,acetonitrile, or ethyl acetate.
 3. The method of claim 2, wherein thesolvent comprises ethanol.
 4. The method of claim 2, wherein the solventcomprises tetrahydrofuran, acetone, dichloromethane, acetonitrile, orethyl acetate.
 5. The method of claim 4, wherein the solvent comprisestetrahydrofuran.
 6. The method of claim 5, wherein the solvent comprisesa mixture of tetrahydrofuran and water.
 7. The method of claim 6,wherein the solvent comprises a mixture of about 95/5tetrahydrofuran/water.
 8. The method of claim 4, wherein the solventcomprises dichloromethane.
 9. The method of claim 4, wherein the solventcomprises acetonitrile.
 10. The method of claim 4, wherein the solventcomprises ethyl acetate.
 11. The method of claim 10, wherein the solventcomprises a mixture of ethyl acetate and methanol.
 12. The method ofclaim 11, wherein the solvent comprises a mixture of about 6/1 ethylacetate/methanol.
 13. The method of claim 4, wherein the solventcomprises acetone.
 14. The method of claim 13, wherein the solventcomprises a mixture of acetone and water.
 15. The method of claim 14,wherein the solvent comprises a mixture of about 95/5 acetone/water. 16.The method of claim 1, wherein the crystallized (R)-modafinil isisolated by filtration.
 17. The method of claim 1, wherein the isolated(R)-modafinil has an enantiomeric excess of at least about 99.5%. 18.The method of claim 1, wherein the isolated (R)-modafinil has anenantiomeric excess of at least about 99.8%.
 19. The method of claim 4,wherein the isolated (R)-modafinil has an enantiomeric excess of atleast about 99.5%.
 20. The method of claim 4, wherein the isolated(R)-modafinil has an enantiomeric excess of at least about 99.8%. 21.The method of claim 1, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 98%.
 22. The method of claim 1,wherein the (R)-modafinil in step (a) has an enantiomeric excess of lessthan about 97%.
 23. The method of claim 1, wherein the (R)-modafinil instep (a) has an enantiomeric excess of less than about 96%.
 24. Themethod of claim 1, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 95%.
 25. The method of claim 2,wherein the (R)-modafinil in step (a) has an enantiomeric excess of lessthan about 98%.
 26. The method of claim 2, wherein the (R)-modafinil instep (a) has an enantiomeric excess of less than about 97%.
 27. Themethod of claim 2, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 96%.
 28. The method of claim 2,wherein the (R)-modafinil in step (a) has an enantiomeric excess of lessthan about 95%.
 29. The method of claim 3, wherein the (R)-modafinil instep (a) has an enantiomeric excess of less than about 98%.
 30. Themethod of claim 3, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 97%.
 31. The method of claim 3,wherein the (R)-modafinil in step (a) has an enantiomeric excess of lessthan about 96%.
 32. The method of claim 3, wherein the (R)-modafinil instep (a) has an enantiomeric excess of less than about 95%.
 33. Themethod of claim 4, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 98%.
 34. The method of claim 4,wherein the (R)-modafinil in step (a) has an enantiomeric excess of lessthan about 97%.
 35. The method of claim 4, wherein the (R)-modafinil instep (a) has an enantiomeric excess of less than about 96%.
 36. Themethod of claim 4, wherein the (R)-modafinil in step (a) has anenantiomeric excess of less than about 95%.
 37. The method of claim 1,further comprising the step of recrystallizing the isolated crystallized(R)-modafinil.
 38. The method of claim 2, further comprising the step ofrecrystallizing the isolated crystallized (R)-modafinil.